scholarly journals Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures

2020 ◽  
Author(s):  
Ayana T Ruffin ◽  
Anthony R Cillo ◽  
Tracy Tabib ◽  
Angen Liu ◽  
Sayali Onkar ◽  
...  
Keyword(s):  
B Cells ◽  
Single Cell ◽  
Antitumor Immunity ◽  
Spatial Organization ◽  
Environmental Carcinogens ◽  
Transitional State ◽  
Rnaseq Data ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractCurrent immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.

scholarly journals B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ayana T. Ruffin ◽  
Anthony R. Cillo ◽  
Tracy Tabib ◽  
Angen Liu ◽  
Sayali Onkar ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
B Cells ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Spatial Organization ◽  
Neck Squamous Cell Carcinoma ◽  
Transitional State ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractCurrent immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.

scholarly journals Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis

2021 ◽  
Vol 8 ◽  
Author(s):  
Rami Mustapha ◽  
Kenrick Ng ◽  
James Monypenny ◽  
Tony Ng
Keyword(s):  
Antitumor Immunity ◽  
Cancer Metastasis ◽  
Potential Role ◽  
Cancer Invasiveness ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Cancer Dissemination ◽  
Alternative Routes ◽  
Biomechanical Factors

Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics.

scholarly journals Tertiary lymphoid structures critical for prognosis in endometrial cancer patients - a TransPORTEC study

2021 ◽  
Author(s):  
Nanda Horeweg ◽  
Hagma Workel ◽  
Dominik Loiero ◽  
David Church ◽  
Lisa Vermij ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
B Cells ◽  
Cox Regression ◽  
Pivotal Role ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
L1cam Expression

Abstract B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigated the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells showed presence of activated/memory B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis showed association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence showed L1CAM expression in mature TLS localized in the myometrial wall or at the tumor invasive border, independent of L1CAM expression the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank were evaluated. TLS were found in 19%, predominantly in mismatch-repair deficient and polymerase-epsilon mutant EC. Multivariable Cox regression analysis showed strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.Statement of significance Tertiary lymphoid structures have a pivotal role in the immune response against endometrial cancer. Presence of mature tertiary lymphoid structures can be easily assessed using L1CAM immunohistochemistry and has independent favorable predictive value for recurrence and endometrial cancer-specific survival.

scholarly journals Tertiary Lymphoid Structures in Cancer: The Double-Edged Sword Role in Antitumor Immunity and Potential Therapeutic Induction Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Wendi Kang ◽  
Zhichao Feng ◽  
Jianwei Luo ◽  
Zhenhu He ◽  
Jun Liu ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Antitumor Immunity ◽  
Close Association ◽  
Germinal Centers ◽  
Vital Role ◽  
Cancer Development ◽  
Multiple Strategies ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

The complex tumor microenvironment (TME) plays a vital role in cancer development and dramatically determines the efficacy of immunotherapy. Tertiary lymphoid structures (TLSs) within the TME are well recognized and consist of T cell-rich areas containing dendritic cells (DCs) and B cell-rich areas containing germinal centers (GCs). Accumulating research has indicated that there is a close association between tumor-associated TLSs and favorable clinical outcomes in most types of cancers, though a minority of studies have reported an association between TLSs and a poor prognosis. Overall, the double-edged sword role of TLSs in the TME and potential mechanisms need to be further investigated, which will provide novel therapeutic perspectives for antitumor immunoregulation. In this review, we focus on discussing the main functions of TLSs in the TME and recent advances in the therapeutic manipulation of TLSs through multiple strategies to enhance local antitumor immunity.

scholarly journals Tertiary Lymphoid Structures as a Predictive Biomarker of Response to Cancer Immunotherapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Trüb ◽  
Alfred Zippelius
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Tumour Response ◽  
Predictive Biomarker ◽  
Exciting Field ◽  
Inflammatory Conditions ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Cancer Immunotherapies

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations which are formed under long-lasting inflammatory conditions, including tumours. TLS are composed predominantly of B cells, T cells and dendritic cells, and display various levels of organisation, from locally concentrated aggregates of immune cells, through clearly defined B cell follicles to mature follicles containing germinal centres. Their presence has been strongly associated with improved survival and clinical outcome upon cancer immunotherapies for patients with solid tumours, indicating potential for TLS to be used as a prognostic and predictive factor. Although signals involved in TLS generation and main cellular components of TLS have been extensively characterised, the exact mechanism by which TLS contribute to the anti-tumour response remain unclear. Here, we summarise the most recent development in our understanding of their role in cancer and in particular in the response to cancer immunotherapy. Deciphering the relationship between B cells and T cells found in TLS is a highly exciting field of investigation, with the potential to lead to novel, B-cell focused immunotherapies.

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